Metastatic colorectal cancer (CRC) is difficult to treat and patients have few long term effective therapeutic options. The aggressiveness of this disease is in part driven by the aberrant expression of oncoproteins. At the molecular level, cap-dependent translation of the precursor oncogenic mRNAs is frequently activated. Specifically this occurs via 4E-BP1 phosphorylation which, when not phosphorylated, functions as a mRNA translation repressor downstream from mTOR. We recently discovered that activated signaling via the PI3K/AKT and RAS/RAF/MEK/ERK pathways cooperate to promote CRC progression by convergent phosphorylation of 4E-BP1. Our work further demonstrated that 4E-BP1 phosphorylation-mediated oncogene translation functions as a critical node that integrates oncogenic signals of the AKT and ERK pathways for CRC tumorigenesis and metastasis. Moreover, we found that CRC resistance to upstream kinase targeted therapy is associated with incomplete inhibition of 4E-BP1 phosphorylation. Notably, genetic blockade of cap-dependent translation by a dominant active and non-phosphorylated 4E-BP1 mutant can effectively suppress tumor growth and metastasis in the mouse models of CRC. Our overarching hypothesis is that directly targeting 4E-BP1 phosphorylation- mediated oncogene translation represents a novel strategy for cancer drug development and therapy. Using a cap-dependent translation-based reporter assay, we recently identified naturally occurring pyranonaphthoquinones that act as selective inhibitors of 4E-BP1 phosphorylation in a manner that is mechanistically distinct to existing mTOR inhibitors. The primary goals of the proposed studies are to determine the fundamental mechanism of pyranonaphthoquinone-based inhibition of 4E-BP1 phosphorylation and identify optimized analogs with suitable in vitro and in vivo potency and selectivity. Cumulatively, the proposed studies offer high potential for the identification and development of structurally and functionally novel agents to target the translational control of CRC progression and metastasis with the potential to define new molecular probes and early stage leads for first-in-class targeted therapies to treat CRC.